5{8 {60 -(p-substituted benzoyl)-p-substituted benzylamino{9 -1,3-dimethylpyrazoles

ABSTRACT

1,3-Dimethyl-4,5-di(p-substituted phenyl)-6H-pyrrolo(2,3c)pyrazoles and novel intermediates useful in their synthesis. The compounds are useful as anti-inflammatory and anti-pyretic agents.

United States Patent 1 Swett et al.

[ Oct. 9, 1973 5[a-(P-SUBSTITUTED BENZOYL )-P-SUBSTITUTED BENZYLAMINO l,3- DIMETHYLPYRAZOLES [75] Inventors: Leo Ralph Swett, Waukegan, 111.;

Gerard Yvon Paris, Duvernay, Quebec, Canada [73] Assignee: AbbottLaboratories, North Chicago, 111.

22 Filed: May 30, 1972 211 App1.No.:257,73l

Related U.S. Application Data I [62] Division of Ser. No. 112,767, Feb.4, 1971, Pat. No.

[52] U.S. C1 260/310 R [51] C07d 49/38 [58] Field of Search 260/310 R[56] References Cited OTHER PUBLICATIONS Balaban Chem. Abst. V01. 72,No. 1006572 (1970). QD1.A51

Brown et a1. Chem. Abst. V01. 43, c01umns'217-221 (1949).QD1.A51

(1956). QD241J6 Reimlinger et a1. Liebigs Ann. Chem. Vol. 720, pages117-123 (1968).QD1.L7 Solomons et a1. J. Amer. Chem. Soc. Vol. 87, pages528-531 (1965). QDl.A5

' Szmuszkovicz et a1. .1. Med. Chem. Vol. 9, pages 527-536 (1966). ES1J5Primary Examiner-Natalie Trousof Attorney-Robert L. Niblack [57]ABSTRACT 1 ,3-Dimethy1-4,5-di(p-substituted pheny1)-6H-pyrro1o[2,3-c-]pyrazo1es and novel intermediates useful in theirsynthesis. The compounds are useful as anti-inflammatory andanti-pyretic agents.

2 Claims, No Drawings 1. s'la- -sunsrrrurau' BENZOYU-P-SUBSTITUTEDBENZYLAMINO1-1,S-DIMETHYLPYRAZOLES- CROSS-REFERENCE TORELATED-APPLICATION This application is a division of co-pendingapplication, Ser. No. 112,767, filed Feb. 4,1971, nowUS. Pat. No.3,701,785.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel1,3-dimethyl4;5-di(-psubstituted phenyl)-6H-pyrrolo[2,3-c]pyrazolesrepresented by the formula CHHTIFQ wherein R is hydrogen, C -C alkyl,.C,-,C .alkoxy, or halo; and "R is benzoyl, halo-substitutedbenzoyl,di( -C )alkylamino(C,-C )a1kyl; 2'-thiophenecarbonyl; hydro'gen or C -Calkyl.

The term C -C alkyl refers to straight andbranched chain alkylsand'includes methyl, ethyl,'.n4 propyl, iso-propyl, n-butyl, sec-butyland-tert-butyl.

The term C C, alkoxy includes methoxy, ethoxy, propoxy and butoxy.

wherein k tis as defined" herein above are novel compounds which'areuseful asintermediates in-the synthesisof the final'products l' ('4'and-"5);

The following examplesfurther illustrate the presentinvention:

' Example 1" 5'-[a-(p-Methoxybenzoyl) p-Methoxybenzylamino]-133-Dimethylpyrazole Hydrochloride A solution of p-anisoin-(27.2'g.,0.10 mole), 1 ,3-

dimethyFS-aminopyrazole (12.2 g., 0.1 1 mole) and- .p-toluene-sulfonicacidmonohydrate (0.95 g., 0.005 mole)'=in-benzene (-100 ml.) wasrefluxed under nitrogen atmosphere for 48 hours usinga Barrett trap tocol- The term halo as used herein includes chloro,

fluoro, bromo and iodo. The compounds of this invention are usefulas'antiinflammatory and anti-pyretic agents whenadrninistered to mammalianpatients in dosages" of from 10 to 50 mg./kg. of body weight daily,preferably in'divided dosages (i.e., 175 to 875mg. four-times daily);The. an-

ti-inflammatory activity of the compoundswasestablished in thecarrageenin rat paw edema test (Winter-et al., Proc. Soc. Exp. Biol.Med. 111', 554119621). 1

The anti-pyretic activity was establishedby the yeastinduced fever testin rats. I

The preferred'method ofpreparing the compounds of this invention isrepresented by the followingreaction scheme:

lect thewater formed'(-1' ml;). The reaction mixture was filteredand thefiltrate was evaporated to dryness to yield an oil (37.8g. A partof thisoil-was dissolved in alcohol and' treated with ethanolic picric acid.The picrate melted at 168 1 69. Analysis Calcd. for C H N O L C, 54.54;H; 4;41'; N, 14.14; 0, 26.92

Found: C, 54.58; H; 4.50; N, 14.20; 0, 26.67

This- 'picrate was dissolved-in methanol and treated with amberlite IRA400 resin'in the OH'form (previously washed' with' methanol); The resinwas filtered 'andthe filtrate was evaporated to dryness. The oilyresidue was'dissolv'ed in ether and anhydrous hydrogen chloride wasbubbled through the solutiori'to give the hydrochloride salt, m-.p.230-3 2 (from alcohol). Analysis Calcd. for C ll- 6N 0 C, 62.76; H,6.02; N, 10.46

Found: C, 62.61; I-I, 6.06; N, 10.60

Example 2 S-[d-(p-Chlorobenzyol)-p-Chlorobenzylamino]1,3-

Dimethylpyrazole Example 3-[a-(p-Methylbenzoyl)-p-Methylbenzylamino]-1,3- DimethylpyrazoleHydrochloride A solution of 4,4'-dimethylbenzoin (14.4 g., 0.060 mole),l,3-dimethyl-5-aminopyrazole (7.3 g., 0.066 mole) and p-toluenesulfonicacid monohydrate (0.57 g., 0.003 mole) was refluxed in benzene (80 ml.)for 24 crude solid was treated with water, filtered and crystallizedfrom alcohol, m.p. 226-228.

hours. The picrate was obtained as described in Exampie 1, m.p. 195-197.Analysis Calcd. for C11H2QHO5Z C, 57.65; H, 4.66; N, 14.94

Found: C, 57.68; H, 4.65; N, 14.92

The picrate was converted to the free base and to the hydrochloride saltas described in Example 1, m.p. 223-225.

Example 4 1,3 -Dimethyl-4,5-di(p Methoxyphenyl)-6H-Pyrrolo-[2,3-c]Pyrazole A stirred mixture of crude 5-[a-(p-methoxybenzoyl)-'p-methoxybenzylaminol-l ,3-dimethylpyrazole (7.3- g.,

0.02 mole), aniline (5.59 g., 0.06 mole) and aniline hydrobromide (1.7g., 0.01 mole) was heated at 170 for 3 hours. The reaction mixture wasevaporated to dryness under vacuum to remove the excess aniline. Theviscous residue was dissolved'in 100 ml. of methanol and treated with 50ml. of amberlite IRA-400 resin in the OH form (previously washed withmethanol). The resin was removed by filtration. The filtrate was evaporated to dryness to yield an oil which was treated with 200 ml. ofether. The insoluble pyrrolo[2,3-c]pyrazole was filtered. Yield 2.5 g.(35 percent) m.p. 230232. Analysis Calcd. for C l-1 N 0 C, 72.60; H,6.09; N,

.Found: C, 72.42; H, 6.14; N, 12.04; 0, 9.03

Example 5 1,3-Dimethyl-4,5-di-(p-chlorophenyl)-6H-pyrrolo-['2,3-c]pyrazole Analysis Calcd. for c,,H,,c1,N,= C, 64.06; H, 4.24; N',l 1.79-

Found: C, 64.10; H, 4.33; N, 11.64

Example 6.

1,3-Dimethyl-4,5-di(p-tolyl)-6H-pyrrolo[2,3-

clpyrazole A stirred mixture of crude S-[a-(p-methylbenzoyD-pmethyl-benzylamino]-l,3-dimethylpyrazole (19.4 g., 0.058 mole), aniline(16.2 g., 0.174 mole) and aniline hydrobromide (5.1 g., 0.029 mole) washeated at 170 for 3 hours. The product was isolated as described inExample 4. Yield 5.5 g., m.p. 238-240' (from alcohol). Analysis Calcd.for C l-l N z C, 79.97; H, 6.71; O, 13.32

Found: C, 79.71; H, 6.77; O, 13.35

Example 7 l ,3-Dimethyl-4,5-diphenyl-6H-pyrrolo 2 ,3-c lpyrazole Asolution of benzoin (21.23 g., 0.10 mole), 1,3- dimethyl-S-aminopyrazole(12.2 g., 0.10 mole) and p-toluene-sulfonic acid monohydrate (0.95 g.,0.005 mole) in ml. of benzene was refluxed for 14 hours under nitrogenatmosphere (1.6 ml. of water was collected).-The reaction mixture wasevaporated to dryness to yield an oil.

A part of the crude oil (12.22 g., 0.04 mole) was heated with aniline (11.8 g., 0.12 mole) and aniline hydrobromide (3.42 g., 0.02 mole) at for3 hours. The product was isolated as described in Example 4, except thatthe residual oil was dissolved in a minimum of alcohol and let stand.Yield 4.0 g., (35 percent), m.p. 130, solidified and melted at 2l021 1.

Analysis Calcd. for C H N C, 79.41; H, 5.97; N,

Found: C, 79.35; H, 5.96; N, 14.44

To a stirred solution of 1,3-dimethyl-4,5-diphenyl-6H-pyrrolo[2,3-c]pyrazole (1.44 g., 0.005 mole) in 24 ml. ofN,N-dimethylformamide was added sodium hydride (0.23 g., 0.005 mole).The reaction mixture was stirred for 1 hour at 25. Methyl iodide (0.71g., 0.005 mole) dissolved in 10 ml. of N,N-dimethylformamide was addeddropwise. After the addition was over, the stirring was continued for 17hours at room temperature. Evaporation of the solvent yielded a solidwhich was crystallized from alcohol, 0.6 g. (40 percent), m.p. 176-l77.

Analysis Calcd. for C H N C, 79.70; H, 6.35; N, 13.94

Found: C, 79.62; H, 6.58; N, 13.74

Example 9 1,3-Dimethyl-4,5-diphenyl-6-(p-chlorobenzoyl)-pyrrolo[2,3-c]pyrazole The reaction of l,3-dimethyl 4,5-diphenyl-6H-pyrrolo[2,3-c]pyrazole (1.44 g., 0.005 mole), sodium hydride (0.23 g.,0.005 mole) and p-chlorobenzoyl chloride (0.88g., 0.005 mole) inN,N-dimethylformamide (20 m1.), as described in Example 8 yielded 1.5

g., (70 percent) of product, m.p. l68169. The analytical sample meltedat 170171, (from alcohol).

Analysis Calcd. for C H ClN O; C, 73.32; H, 4.73; N,

Found: C, 73.21; H, 4.67; N, 9.90

Example 1,3 ,6-Trimethyl-4,5-di-(p-methoxyphenyl)-pyrrolo- The reactionof 1,3-dimethyl-4,5-di-(p-methoxyphenyl)-6-H-pyrro1o[2,3-c]pyrazole (3.5g., 0.01 mole), sodium hydride (0.46 g., 0.01 mole) and'methyl iodide(1.4 g., 0.01 mole) in N,N-dimethylformamide, as described in Example 8,gave 2.7 g., (75 percent) of product, m.p. l79-181. The analyticalsample inelted at l80l82 (from alcohol).

Analysis Calcd. for C H N O C, 73.11; H, 6.41; N, 11.63

FoundzC, 72.89; H, 6.51; N, 11.73

Example 1 1 1 ,3-Dimethy1-4,5-di(p-methoxyphenyl-6-benzoy1pyrrolo-[2,3-c lpyrazole The reaction of1,3-dimethyl-4,5-di(pmethoxyphenyl)-6H-pyrrolo[2,3-c1pyrazole 1.74 g.,0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride(0.71 g., 0.005 mole) in 20 ml. of N,N-dimethylformamide, as describedin Example 8, yielded 1.5 g., (66 percent) m.p. l46150. The analyticalsample melted at 162163. Analysis Calcd. for G il -N 0 C, 74.48; 9.31;0, 10.63 1

Found: C, 74.28; H, 5.69; N, 9.24; O, 10.70

I Example 12 1,3-Dimethyl-4,5-di-(p-methoxyphenyl)-6-(pchlorobenzoyl)pyrrolo[2,3-clpyrazoleThe reaction of 1,3-dimethyl-4,5-di-(pmethoxyphenyl)-6H-pyrrolo[2,3-c]pyrazole (3.47 g.,0.01 mole), sodium hydride (0.46 g., 0.01 mole) and p-chlorobenzoylchloride (1.75 g., 0.01 mole) in 30 ml. of N,N-dimethylformamide, asdescribed in Example 8, gave 2.7 g. (56 percent) of product, m.p.176l78. The analytical sample melted at l78-179. AnalysisCal'cd. for C HClN O C, 69.20; H, 4.98; Cl, 7.30; N, 8.65; O, 9.88

Found: C, 69.34; H, 4.98; C], 7.52; N, 8.82; O, 10.17

Example 13 1,3 ,6-Trimethyl-4,5-di-(p tolyl)pyrrolo[2,3-c]- pyrazole Thereaction of l,3-dimethyl-4,5-di-(p-tolyl)-6H- pyrrolo[2,3-c1pyia2ole(1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and methyliodide (0.71

g., 0.005 mole) in 25 ml. of N,N-dimethylformamide as described inExample 8 yielded 0.7 g. (44 percent) of product, m.p.l82l84.

Analysis Calcd. for c n m; C, 80.21;

Found: C, 80.40; H, 7.18; N, 12.78

Example 14 cent) of product, m.p. l98200.

chlorophenyl)-6H pyrrolo[2,3-c]pyrazole 0.005 mole sodium hydride (0.23g., 0.005 mole) and p-chlorobenzoyl chloride (0.88 g., 0.005 mole) in 25Example 15 l,3-Dimethyl-4',S-di-(p-tolyl)-6-(p-chlorobenzoyl)-pyrrolo[2,3-c]pyrazole The reaction in'l',3-dimethyl-4,5-di-(p-tolyl)-6H- pyrrolo[2,3-c]pyrazole (1.6 g.,0.005 mole), sodium hydride (0.23 g., 0.005 mole) and p-chlorobenzoylchloride (0.88 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide gave0.4 g., of product (17 percent), m.p. 204 -206".

Analysis Calcd. for C H C1N O: C, 74.08; H, 5.33; N, 9.26

Found: C, 74.20; H, 5.42; N, 9.29

. Example 16 1 ,3,6-Trimethy1-4,5-di( p-chlorophenyl)-pyrrolo-[ 2,3-

. c]pyrazole The reaction ofl,3-dimethyl-4,5-di-(pchlorophenyl)-6H-pyrro1o[2,3-c]pyrazole (1.4 g.,0.0039 mole), sodium hydride (0.18 g., 0.0039 mole) and methyl iodide(0.55 g., (0.0039 mole) in 20ml. of

N,N-dimethylfor'mamide gave the product (0.7 g.) 'in 49 percent yield,m.p. 208-210. 7 Analysis Calcd. for c r-1, 0 1%: C, 64.87; H, 4.63; N,11.35

Found: C, 64.99; H; 4.68; N, 11.42

Example 17l,3-Dimethyl-4,5-di-(p-chlorophenyl)-6-benzoylpyrrolo[2,3-o1pyrazole Thereaction of1,3-dimethy1-4,5-di-(pchlorophenyl)-6H-pyrrolo[2,3-c]pyrazole (1.8 g.,

p 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride(0.71 g., 0.00.5 mole) in 25 ml. of N,N-dimethylformamide yielded 0.93g. (40 percent) of the desired'product, m.p. 188-190. Analysis Calcd.for C H Cl N O: C, 67.83; H, 4.16; N,

Found: C, 68.08; H, 4.24; N, 9.21

, Example 18 l ,3-Dimethy1-4,5-di-(p-chlorophenyl)6-(p-chlorobenzoyl)-pyrrolo[2,3 c]pyrazole of 1 ,3-dimethyl-4,5-di-(p- QThe reaction ml. of N,N-dimethylformamide as described in Example 8 gavethe expected product in 32 percent yield (0.8 g.), m.p. l86-188.Analysis Calcd. for c,,11,,c1,N,0. 8.49

Found: C, 63.31; H, 3.72; N, 8.66

Example 19 To a stirred solution of 1,3-dimethyl 4,5-di-(pmethoxyphenyl)-6H-pyrrolo[2,3-c1pyrazole (3.5 g., 0.01 mole) in 25 ml.of N,N-dimethylformamide was added sodium hydride (0.46 g., 0.01 mole).The reaction mixture was stirred for 2 hours at 25. Diethylaminethylchloride (1.4 g., 0.01 mole) dissolved in 25 ml. ofN,N-dimethylformamide was added dropwise. After the addition was over,the stirring was continued for 20 hours at room temperature. Evaporationof the solvent yielded an oil. Extraction with (high boiling)petroleum-ether and evaporation of the petroleum-ether layer yielded acrude solid. Crystallization with petroleum-ether yielded 1.7 g. (37percent) or product, m.p. l08-l 10. Analysis Calcd. for C E- N 0,: C,72.62; H, 7.67; N, 12.55

Found: C, 72.61; H, 7.87; N, 12.55

Example 20 l ,3-Dimethyl-4,5-di-(p-methoxyphenyl)-6-( 2-thiophenecarbonyl )pyrroloI 2 ,3-c ]pyrazole To a stirred solution ofl,3-dimethyl-4,5-di- (pmethoxyphenyl)-6H-pyrrolo[2,3-c]pyrazole (3.5 g.,0.01 mole) in 25 ml. of N,N-dimethylformamide was added sodium hydride(0.46 g., 0.01 mole). The reaction mixture was stirred overnight at roomtemperature. 2Thiophenecarbonyl chloride 1.5 g., 0.01 mole) in 25 ml. ofN,N-dimethylformamidewas added dropwise. After the addition was over,the stirring was continued for 2 hours. Evaporation of the solventyielded an oil. A solid (crude) formed when the oil was treated with dryether. Crystallization of the solid with alcohol 8 7 yielded 1.4 g. (31percent) of product, m.p. l80-l82. Analysis Calcd. for c,,H,,N,o,s: C,68.25; H, 5.07; N, 9.18

Found: C, 68.41; H, 5.26; N, 9.32 The compounds of the present inventioncan be incorporated into various pharmaceutically acceptable dosageforms such as tablets, capsules, pills, suspensions and the like forimmediate or sustained release,

by combining them with suitable carriers or diluents according tomethods well known in the art. In addition to the active agent and thepharmaceutically. acceptwherein each R is hydrogen, [C -C ,alkyl of l-4carbon atoms, [C -C alkoxy of l- 4 carbon atoms or halo.

2. A compound in accordance with claim 1:S-[a-(pmethoxybenzoyl)-p-methoxybenzylamino]-l ,3- dimethylpyrazole.

2. A compound in accordance with claim 1: 5-( Alpha-(p-methoxybenzoyl)-p-methoxybenzylamino)-1,3-dimethylpyrazole.